Do people with hereditary cancer syndromes inform their at-risk relatives? A systematic review and meta-analysis

Purpose To evaluate rates of familial disclosure of hereditary cancer syndrome information. Methods A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). Key electronic databases were searched to identify studies evaluating hereditary cancer syndrome cascade relative disclosure. Eligible studies were subjected to meta-analysis. Results Thirty-four studies met inclusion criteria. Among 11,711 included relatives, 70% (95% CI 60 - 78%) were informed of their risk of carrying a cancer-associated pathogenic variant; of 2,875 relatives informed of their risk who were evaluated for uptake of cascade testing, 43% (95% CI 27 - 61%) completed testing. Rates of disclosure were higher among female vs male relatives (79% [95% CI 73% - 84%] vs 67% [95% CI 57% - 75%]) and first-degree vs second-degree relatives (83% [95% CI 77% - 88%] vs 58% [95% CI 45 – 69%]). Conclusion Nearly one-third of at-risk relatives remain uninformed of their risk of carrying a cancer-associated pathogenic variant. Even among those informed, fewer than half subsequently complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Innovation Five studies evaluating interventions to improve disclosure rates were generally ineffective. Urgent work is needed to elucidate barriers to relative disclosure by probands to develop targeted interventions that can optimize proband-mediated cascade genetic testing rates.


Introduction
Cascade genetic testing refers to the process of extending genetic testing to relatives of probands in whom germline pathogenic variants have been identified. In the context of cancer-predisposing pathogenic variants, cascade genetic testing offers the opportunity for cancer surveillance and riskreduction strategies that can decrease cancer morbidity and mortality [1][2][3][4]. There are several hereditary cancer syndromes with evidence-based surveillance guidelines to reduce cancer risk [5,6]. Furthermore, the Centers for Disease Control and Prevention Office of Public Health Genomics has designated cascade genetic testing for hereditary breast and ovarian cancer as well as Lynch syndrome as a tier one genomic application, defined as having significant potential for positive impact on public health [7]. Risk-reducing bilateral salpingo-oophorectomy and bilateral mastectomy are associated with a decreased risk of breast and ovarian cancer in individuals with BRCA1/2 pathogenic variants, with risk-reducing bilateral salpingo-oophorectomy associated with a significantly lower all-cause mortality rate in this population [2]. For individuals with Lynch syndrome, surveillance with colonoscopy has been shown to decrease the risk for colorectal cancer, prevent colorectal cancer deaths, and decrease overall mortality [3,4].
Approximately four million people currently living in the United States harbor a cancer-associated pathogenic variant; however, the majority of these individuals are not aware [8][9][10]. Prediction modeling suggests that genetic testing at time of cancer diagnosis combined with cascade genetic testing of 70% of firstand second-degree relatives could result in identification of all carriers in less than a decade [10,11]. However, the literature suggests that only 35% of at-risk relatives currently complete cascade genetic testing for cancer syndromes [12]. Low rates of cascade genetic testing represent a critical missed opportunity in oncology care. Additionally, the literature suggests that racial and ethnic minorities and those of low socioeconomic status experience even greater underutilization of all aspects of genetic services including cascade testing [12,13].
Although relatives can learn of the presence of a cancer-associated pathogenic variant in their family without being informed by the proband, for PEC Innovation 2 (2023) 100138 example via direct contact by healthcare providers, disclosure by probands is the most common method of information dissemination within families [11]. Disclosure of genetic risk information by probands to their relatives is the critical first step in initiating the process of proband-mediated cascade genetic testing. As such, we aimed to systematically review the literature about disclosure patterns among families with cancer-associated pathogenic variants and conduct a meta-analysis on the pooled rates of disclosure and uptake of cascade testing among relatives informed of their risk, which has not previously been reported.

Overview
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was preregistered with PROSPERO (registration no.: CRD42020134276) [14]. A comprehensive literature search was devised with the assistance of a librarian and conducted on July 23, 2021, using the following bibliographic databases with no limit on year of publication:

Inclusion and exclusion criteria
Eligible manuscripts included all primary English language studies that assessed cascade genetic testing for cancer-associated pathogenic gene variants with a focus on disclosure of genetic testing results to at-risk relatives. All non-primary research studies including commentaries, case reports, systematic reviews, and meta-analyses were excluded. A comprehensive review of reasons for exclusion of studies can be found in the PRISMA flow diagram (Figure 1).

Data extraction
All manuscripts were independently evaluated for inclusion by two reviewers and disagreements were discussed with a third reviewer. Data were independently extracted by two different reviewers, with a third reviewer checking the final extracted data for accuracy.

Risk of bias assessment
All included studies were evaluated for risk of bias in their design, conduct, and analysis using the Joanna Briggs Institute's Critical Appraisal tools [15].

Statistical analysis
Meta-analyses for the proportion of probands that informed at least one at-risk relative, the proportion of at-risk relatives who were successfully informed and proportion of at-risk relatives who completed genetic testing among those informed were conducted using R software (Version 3.6.1 [07/05/19], R Foundation for Statistical Computing, Vienna, Austria). Statistical heterogeneity was tested through the chi-square test (i.e., Cochrane Q test), and a P value < 0.2 was used to indicate the presence of heterogeneity. Statistical heterogeneity was also assessed by the inconsistency statistic (I 2 ). A random effects analysis was used to calculate pooled proportions. The random effects analysis is more conservative and allows for more variability in the individual study proportion estimates when generating the pooled proportion. The pooled proportion was calculated using the Freeman-Tukey Double arcsine transformation, and the 95% CI was calculated using the Clopper-Pearson interval. The DerSimonian-Laird estimator was used to estimate the between-study variance. For the outcome proportions of interest, the results of each study were expressed as binary proportions with exact 95% CIs. For each meta-analysis, a funnel plot was constructed and reviewed, displaying the study proportion against study precision, estimated by the standard error, to assess for publication bias.

Study characteristics
A total of 34 publications of original research were included in our systematic review, of which, data from 31 publications were included in our meta-analyses. Five studies evaluated interventions to improve disclosure rates among families. Although data from intervention arms of all five studies were excluded from our meta-analysis of non-intervention studies to avoid biasing results, two intervention studies utilized historical controls for comparison, data from which were included in our meta-analysis of non-intervention studies. Across all 34 included articles, study designs included 24 cross-sectional studies, 9 prospective studies, and 1 retrospective study. Study publication dates ranged from 2003-2020 and spanned 10 countries: United States (20), France (3), Australia (3), Netherlands (2), Belgium (1), Finland (1), Israel (1), Malaysia (1), Sweden (1), and the United Kingdom (1). Twenty studies evaluated disclosure rates among relatives at risk for hereditary breast and ovarian cancer only, 4 evaluated disclosure rates among those at risk for Lynch syndrome only, 1 among those at risk for hereditary pancreatic cancer only, and 9 included mixed hereditary cancer syndrome populations (Table 1).

Cumulative patient characteristics
A total of 3,779 probands and 11,711 relatives were evaluated for disclosure of genetic test results. The median age of probands across all studies was 50 years and the median age of relatives across all studies was 33.5 years. Among 31 studies that included information on proband biologic sex, 5,118 (83.9%) were female and 981 (16.1%) were male. Among 11 studies that included information on relative biologic sex, 2,094 (50.5%) were female and 2,051 (49.5%) were male.

Additional factors associated with disclosure
Other studies identified factors associated with disclosure of genetic test results, but the data were either too limited or heterogenous to be metaanalyzed. Four studies reported on the association between race and ethnicity and results disclosure. Taber et al. and Cheung et al. reported higher rates of disclosure among White vs non-White families, whereas two studies found no association [23][24][25][26]. Conley et al. studied disclosure patterns among Black families only, finding that 77% of Black probands in their cohort disclosed their genetic test results to at least one relative [27].
Five studies evaluated the impact of proband education level on rates of disclosure. Two studies reported that probands who had at least a college education were more likely to disclose results to relatives when compared to probands whose highest level of education was high school [28,29]. Three studies reported no association between proband education level and disclosure rates [21,25,26].
Two studies evaluated the impact of proband socioeconomic status on disclosure rates. Taber et al. reported that probands with annual incomes higher than $35,000 were more likely to share their genetic test results with relatives when compared to probands with annual incomes lower than $35,000; Cheung et al. reported no association between income and disclosure rates of probands [23,24].

Barriers to disclosure
Sixteen studies reported on barriers that probands faced in disclosing to relatives. The most common barrier to disclosure reported by probands in 10 studies was not being in close contact with relatives, including being estranged and not having relatives' contact details [20][21][22]26,[30][31][32][33][34][35]. Nine studies reported probands' fear of causing their relatives distress or anxiety as a barrier to disclosure [19][20][21][22][26][27][28]30,35]. Six studies reported that probands felt their relatives were either too old or too young to learn of the familial pathogenic variant [17,20,28,32,33,36]. Five studies reported that probands either did not know why it was important to share information about the familial pathogenic variant with relatives or that they felt genetic information was too personal to share [19,20,22,28,30]. Four studies reported probands did not disclose to relatives because they found the topic too distressing to bring up [19,27,30,37]. Other less commonly reported barriers included inferring a lack of interest from relatives and not feeling comfortable sharing complex medical information [19,21,22].

Interventions
Five studies evaluated interventions to assist probands in disclosing information about a familial pathogenic variant to their relatives ( Table 2). A meta-analysis of disclosure rates among intervention studies was not possible due to an inadequate number of studies evaluating sufficiently homogenous interventions and reported outcomes. Two studies evaluated telephone counselling interventions whereby a member of the clinical team counseled the proband via telephone regarding identification of at-risk relatives, underscoring the importance of disclosing results, and providing information about what content to disclose [30,38]. Two studies evaluated the provision of written educational materials such as information about their familial cancer syndrome, information about cost and insurance coverage of genetic testing and letters to share with relatives informing them of their risk [32,39]. One study evaluated in-person counseling of probands to provide them with strategies on how to disclose to relatives, prepare them for relatives' emotional reactions and share   genetic counseling resources with their relatives [40]. Of all these studies, only Forrest et al and Kardashian et al reported positive results of their telephone counseling and written educational resource interventions respectively [30,39].

Risk of bias assessment
Studies were assessed for risk of bias using tools from the Joanna Briggs Institute. Although all studies suffered from risk of bias in at least one domain, most commonly in lack of identification and control of confounders, they were all deemed appropriate to include in this synthesis. The funnel plots for rates of disclosure and uptake of cascade genetic testing suggest underrepresentation of smaller studies ( Supplementary Figures 1-3).

Discussion
We have systematically reviewed the available literature on disclosure of genetic test results by probands to their relatives in the context of  cancer-associated pathogenic variants and found that up to 30% of relatives are not aware of the familial cancer risk. Disclosure of genetic testing results by probands is the obligate prerequisite to the process of proband-mediated cascade genetic testing that can result in early cancer detection and cancer prevention for at-risk relatives. With the majority of cancer-associated pathogenic gene variant carriers in the U.S. unaware of their risk, determining rates of disclosure as well as uptake of genetic testing among those relatives to whom disclosure was made, are essential to characterize the efficiency of cascade genetic testing when the process is mediated by probands [9]. Subsequently, this will enable the field to identify avenues for improvement. To the best of our knowledge, this is the first meta-analysis on rates of disclosure among probands identified to have cancer-associated pathogenic gene variants to their at-risk relatives. Although our prior systematic review and meta-analysis reported uptake rates of cascade genetic testing, uptake rates specifically among relatives who were informed of their risk of carrying a pathogenic gene variant were not reported, and to the best of our knowledge, this is also the first meta-analysis reporting this outcome [12]. Notably, our findings revealed that only 70% of at-risk relatives are aware of their increased risk of carrying a cancer-associated pathogenic gene variant. Furthermore, among those relatives who are successfully informed, only 43% successfully complete genetic testing to define their pathogenic variant status. Probands were more likely to disclose to female vs male relatives, a trend that has also been observed in uptake of cascade genetic testing [12]. Probands were more likely to disclose to first-degree vs more distant relatives, which has also been reported for cascade testing [12]. Limited literature suggested that probands who were non-White, with lower income and lower levels of completed education were less likely to disclose genetic risk information to their relatives; however, other studies found no association. These studies evaluated the impact of race, ethnicity, income and education level on disclosure rates as secondary outcomes and could thus be underpowered for these outcomes. This highlights the need for well-designed studies, specifically evaluating the influence of these factors on relative disclosure rates. Literature on the impact of race, ethnicity, income and education on cascade testing is also sparse; however, limited data suggest similar trends of lower uptake rates among racial and ethnic minorities, relatives with lower income, and those with lower levels of completed formal education [24,[41][42][43][44]. Notably, 75% of probands among all studies that reported on disclosure of genetic test results were identified as White. Lack of inclusion of racially and ethnically diverse populations is a critical issue in cancer genetics research and highlights the need to study disclosure patterns among minority and underserved populations [41,45].
This study should be viewed in light of important limitations. First, disclosure of genetic test results to relatives was reported by probands and not confirmed by relatives for all included studies, and thus the meta-analyzed data are subject to recall bias. Furthermore, funnel plots for both proportion of probands disclosing to at least one at-risk relative as well as proportion of at-risk relatives disclosed to demonstrate a skew towards higher disclosure rates among smaller studies. However, larger studies far outnumbered smaller studies in both these funnel plots, and thus the absence of smaller studies with lower disclosure rates is unlikely to be a significant contributor to publication bias. Finally, although all studies were deemed to be of sufficiently low risk of bias overall to be included in our synthesis, no study was entirely unbiased-every included study suffered from risk of bias in one  or more domain, most commonly failing to identify and control for confounders.

Innovation
Interventions aimed to better equip probands to disclose genetic risk information by providing written or telephone resources were generally ineffective, highlighting the need for studies focused on proband barriers to disclosure so that targeted interventions can be developed.
Recent studies have focused on direct relative contact via clinicians or genetic testing clinical laboratories as a strategy to increase rates of cascade genetic testing [11,12]. Direct relative contact is promising in alleviating barriers such as strained relationships, lack of contact and distress in disclosing to relatives, which we found to be the most commonly reported barriers to disclosure. However, our review suggests that several other factors may contribute to an individual's decision to disclose results to their at-risk relatives including biologic sex, degree of relation and family demographics. It is thus of vital importance to further characterize patterns in and barriers to disclosure to relatives of cancer genetic information in order to develop innovative interventions that can result in equitable improvement in familial disclosure and completion of cascade cancer genetic testing.

Declaration of Competing Interest
Kevin Holcomb reports a relationship with Johnson & Johnson that includes: consulting or advisory.